Decreased PTGDS Expression Predicting Poor Survival of Endometrial Cancer by Integrating Weighted Gene Co-Expression Network Analysis and Immunohistochemical Validation

Ruoyao Zou,1,2 Mingjun Zheng,3 Mingzi Tan,4 Haoya Xu,1,2 Nannan Luan,1 Liancheng Zhu1,2 1Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, People’s Republic of China; 2Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, Liaoning, People’s Republic of China; 3Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany; 4Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, People’s Republic of ChinaCorrespondence: Liancheng ZhuDepartment of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, People’s Republic of ChinaEmail medecin@126.comPurpose: To identify key pathogenic genes and reveal the potential molecular mechanisms of endometrial cancer (EC) using bioinformatics analysis and immunohistochemistry validation.Materials and Methods: Through weighted gene co-expression network analysis (WGCNA), a co-expression network was constructed based on the top 25% variant genes in the GSE50830 dataset downloaded from gene expression omnibus (GEO). GO and KEGG pathway enrichment analyses were performed using the DAVID online tool. Candidate genes were selected using the cytoHubba plug-in of Cytoscape, mRNA expression levels and prognostic values in EC were analyzed by Oncomine, GEPIA, and Kaplan–Meier Plotter database to determine hub genes. One hub gene was validated by immunohistochemical (IHC) staining of 116 paraffin-embedded endometrial tissues and TCGA-UCEC cohort. Genes co-expressed with this hub gene were identified by LinkedOmics. Finally, its correlation with immune infiltration was evaluated by TIMER.Results: Three co-expression modules and five candidate genes in each module were obtained by WGCNA; four hub genes were identified (LGR5, SST, ZNF558, and PTGDS). The mRNA levels of LGR5 and SST were significantly upregulated in EC, whereas those of ZNF558 and PTGDS were significantly downregulated; the expression of all four genes was associated with EC prognosis. Further validation demonstrated that PTGDS was significantly downregulated in the EC group compared with the atypical hyperplasia and normal endometrial groups, and its low expression was an independent risk factor for worse prognosis of EC. Biological function analysis indicated that PTGDS might be involved in the adaptive immune response, leukocyte migration, as well as in the regulation of cell adhesion molecules and chemokine signaling. Additionally, PTGDS expression was positively correlated with immune infiltration status of B cells, CD4+ T cells and macrophages.Conclusion: LGR5, SST, ZNF558, and PTGDS may participate in the development, progression, and prognosis of EC, in which PTGDS may be a novel biomarker and therapeutic target for EC.Keywords: endometrial cancer, bioinformatics analysis, WGCNA, immunohistochemistry, PTGDS